Method of treating hypertension

ABSTRACT

Disclosed herein are compositions and methods for the treatment of pulmonary hypertension, including pulmonary arterial hypertension. The methods include administering to a patient in need thereof an effective amount of Quetiapine or derivative thereof. The compositions include an effective amount of Quetiapine or derivative thereof, in some instances combined with one or more additional agents for the treatment of pulmonary hypertension.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of Indian Application 201721031870,filed on Sep. 8, 2017, the contents of which are hereby incorporated inits entirety.

FIELD OF THE INVENTION

The present invention relates to a method of treatment of pulmonaryhypertension, including pulmonary arterial hypertension, byadministering quetiapine either alone or optionally in combination withone or more other agents. The present invention also pertains tocompositions and kits useful for the treatment of pulmonary arterialhypertension in humans containing quetiapine or derivative thereof,alone or in combination with one or more drugs.

BACKGROUND

Pulmonary arterial hypertension (PAH), one of the five types ofpulmonary hypertension (PH), is a life-threatening disease characterizedby pulmonary vascular remodeling that leads to increased pulmonaryvascular resistance and pulmonary arterial pressure, most oftenresulting in right-side heart failure. It is a progressive conditioncharacterized by elevated pulmonary arterial pressures leading to rightventricular (RV) failure. It is defined at cardiac catheterization as amean pulmonary artery pressure of 25 mm Hg or more. The most commonsymptom associated is breathlessness, with impaired exercise capacity asa hallmark of the disease.

PAH is associated with significant morbidity and mortality. It is causedby complex pathways that culminate in structural and functionalalterations of the pulmonary circulation and increases in pulmonaryvascular resistance and pressure. Many mechanisms can lead to elevationof pulmonary pressures. In PAH, progressive narrowing of the pulmonaryarterial bed results from an imbalance of vasoactive mediators,including prostacyclin, nitric oxide, and endothelin-1. This leads to anincreased right ventricular afterload, right heart failure, andpremature death. Diverse genetic, pathological, or environmentaltriggers stimulate PAH pathogenesis culminating in vasoconstriction,cell proliferation, vascular remodeling, and thrombosis. Currentconcepts suggest that PAH pathogenesis involves three primary processes:vasoconstriction, cellular proliferation/vascular remodeling, andthrombosis.

The molecular mechanism underlying PAH pathophysiology is not known yet,but it is believed that the endothelial dysfunction results in adecrease in the synthesis of endothelium-derived vasodilators such asnitric oxide and prostacyclin. Moreover, stimulation of the synthesis ofvasoconstrictors such as thromboxane and vascular endothelial growthfactor (VEGF) results in a severe vasoconstriction and smooth muscle andadventitial hypertrophy characteristic of patients with PAH.

Between 11% and 40% of patients with Idiopathic pulmonary arterialhypertension [IPAH] and 70% of patients with a family history of PAHcarry a mutation in the gene encoding bone morphogenetic receptor-2(BMPR2). However, penetrance is low, carriers have a 20% lifetime riskof developing pulmonary hypertension. Therefore, “multiple hits” areprobably needed for the development of PAH. In pulmonary hypertensionassociated with left heart disease (PH-LHD), raised left atrialpressures result in secondary elevation of pulmonary pressure. Inpulmonary hypertension owing to lung disease or hypoxia (PH-Lung),raised pulmonary arterial pressures result from mechanisms such asvascular destruction and hypoxic vasoconstriction. In chronicthromboembolic pulmonary hypertension [CTEPH], mechanical obstruction ofthe pulmonary vascular bed, is the primary process. Incidences areestimated to be 1-3.3 per million per year for IPAH and 1.75-3.7 permillion per year for CTEPH; the prevalence of PAH is estimated at 15-52per million. Pulmonary hypertension is more common in severe respiratoryand cardiac disease, occurring in 18-50% of patients assessed fortransplantation or lung volume reduction surgery, and in 7-83% of thosewith diastolic heart failure.

While there is currently no cure for PAH significant advances in theunderstanding of the pathophysiology of PAH have led to the developmentof several therapeutic targets. Besides conservative therapeuticstrategies such as anticoagulation and diuretics, the current treatmentparadigm for PAH targets the mediators of the three main biologicpathways that are critical for its pathogenesis and progression: (1)endothelin receptor antagonists inhibit the upregulated endothelinpathway by blocking the biologic activity of endothelin-1; (2)phosphodiesterase-5 inhibitors prevent breakdown and increase theendogenous availability of cyclic guanosine monophosphate, which signalsthe vasorelaxing effects of the down regulated mediator nitric oxide;and (3) prostacyclin derivatives provide an exogenous supply of thedeficient mediator prostacyclin.

There are various drugs approved for the treatment of PAH: inotropicagents such as digoxin aids in the treatment by improving the heart'spumping ability. Nifedipine (Procardia) and Diltiazem (Cardizem) act asvasodilators and lowers pulmonary blood pressure and may improve thepumping ability of the right side of the heart

Bosentan (Tracleer), ambrisentan (Letairis), macitentan (Opsumit), etc.are dual endothelin receptor antagonist that help to block the action ofendothelin, a substance that causes narrowing of lung blood vessels.There are others which dilate the pulmonary arteries and prevent bloodclot formation. Examples of such drugs are Epoprostenol (Veletri,Flolan), treprostinil sodium (Remodulin, Tyvaso), iloprost (Ventavis);PDE 5 inhibitors such as Sildenafil (Revatio), tadalafil (Adcirca),relax pulmonary smooth muscle cells, which leads to dilation of thepulmonary arteries.

Sildenafil is shown to be efficacious in therapy for humans withpulmonary arterial hypertension (Anna R Hemmes et al J. Expert Review ofCardiovascular Therapy, 4(3), 293-300, 2006)

U.S. Pat. No. 5,570,683 discloses methods for treating or preventingreversible pulmonary vasoconstriction in a mammal such as PAH usingcombination of inhaled nitric oxide and therapeutically-effective amountof a phosphodiesterase inhibitor; wherein said phosphodiesteraseinhibitor is administered before, during, or immediately after nitricoxide administration.

U.S. Pat. No. 7,893,050 discloses therapeutic combinations, comprisingan effective amount of fasudil and sildenafil, for treating pulmonaryarterial hypertension.

European Patent No. EP 1097711B1 discloses the use of sildenafil in themanufacture of a medicament for treating or preventing pulmonaryhypertension.

U.S. Pat. No. 8,324,247 discloses methods for treating pulmonaryarterial hypertension (PAH) by blocking both 5-HT2A and 5-HT2B receptorsin a pulmonary artery such as N-methyl-L-prolinol.

U.S. Pat. Nos. 9,474,752 and 8,377,933 disclose methods for treating apulmonary hypertension condition in a human patient, using combinationof ambrisentan and agent selected from the group consisting ofsildenafil, tadalafil and vardenafil.

Histamine stimulates only H1- and H2-receptors, since combined H1- andH2-receptor antagonism prevented almost all of the cardiovascularactions of histamine. (Tucker A. et al American J of Physiology, 229,1008-1013, October 1975).

In addition to these established current therapeutic options, a largenumber of potential therapeutic targets are being investigated. Thesenovel therapeutic targets include soluble guanylyl cyclase,phosphodiesterases, tetrahydrobiopterin, 5-hydroxytryptamine (serotonin)receptor 2B, vasoactive intestinal peptide, receptor tyrosine kinases,adrenomedullin, rho kinase, elastases, endogenous steroids, endothelialprogenitor cells, immune cells, bone morphogenetic protein and itsreceptors, potassium channels, metabolic pathways, and nuclear factor ofactivated T cells.

Despite a certain success achieved in recent years, many patients withPAH are not adequately managed with existing therapies.

It is an object of the invention to provide a novel therapeutic methodfor the treatment of pulmonary hypertension, including pulmonaryarterial hypertension.

It is an object of the invention to provide novel compositions for thetreatment of pulmonary hypertension, including pulmonary arterialhypertension.

It is an object of the invention to provide a novel therapeutic methodfor the treatment of pulmonary hypertension, including pulmonaryarterial hypertension, using quetiapine.

It is an object of the invention to provide novel compositions for thetreatment of pulmonary hypertension, including pulmonary arterialhypertension, containing quetiapine.

SUMMARY

Disclosed herein are methods for treating pulmonary hypertension, forinstance, pulmonary arterial hypertension, in patients in need thereof.In some instances, the methods include at least partial reduction of thesymptoms associated with pulmonary hypertension, and in some instancesinclude completed elimination of the symptoms associated with pulmonaryhypertension. The methods include the use of quetiapine or a derivativethereof for the treatment of pulmonary hypertension. Also disclosedherein are compositions for the treatment of hypertension, wherein thecompositions include quetiapine or a derivative thereof.

The details of one or more embodiments are set forth in the descriptionsbelow. Other features, objects, and advantages will be apparent from thedescription and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts Right Ventricular Systolic Pressure (RVSP) mmHg forGroups I, II, III, IV, V.

FIG. 2 depicts Right Ventricular Pressure (RVP) mmHg for Groups I, II,III, IV, V.

FIG. 3 depicts Fulton index: Hypertrophy (RV/LV+S) for Groups I, II,III, IV, V.

FIG. 4 depicts Right Ventricle (RV) (g) for Groups I, II, III, IV, V.

FIG. 5 depicts Right Ventricle/body Weight (RV/BW) for Groups I, II,III, IV, V.

DETAILED DESCRIPTION

Before the present methods and systems are disclosed and described, itis to be understood that the methods and systems are not limited tospecific synthetic methods, specific components, or to particularcompositions. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only andis not intended to be limiting.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Ranges may be expressed herein as from “about” oneparticular value, and/or to “about” another particular value. When sucha range is expressed, another embodiment includes, from the oneparticular value and/or to the other particular value. Similarly, whenvalues are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms anotherembodiment. It will be further understood that the endpoints of each ofthe ranges are significant both in relation to the other endpoint, andindependently of the other endpoint.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances where itdoes not.

Throughout the description and claims of this specification, the word“comprise” and variations of the word, such as “comprising” and“comprises,” means “including but not limited to,” and is not intendedto exclude, for example, other additives, components, integers or steps.“Exemplary” means “an example of” and is not intended to convey anindication of a preferred or ideal embodiment. “Such as” is not used ina restrictive sense, but for explanatory purposes.

Disclosed are components that can be used to perform the disclosedmethods and systems. These and other components are disclosed herein,and it is understood that when combinations, subsets, interactions,groups, etc. of these components are disclosed that while specificreference of each various individual and collective combinations andpermutation of these may not be explicitly disclosed, each isspecifically contemplated and described herein, for all methods andsystems. This applies to all aspects of this application including, butnot limited to, steps in disclosed methods. Thus, if there are a varietyof additional steps that can be performed it is understood that each ofthese additional steps can be performed with any specific embodiment orcombination of embodiments of the disclosed methods.

Quetiapine is a psychotropic agent belonging to the chemical class ofdibenzothiazepine derivatives, and it is used in the treatment ofschizophrenia. Quetiapine fumarate is rapidly absorbed after oraladministration, reaching peak plasma concentrations in 1.5 hours.Quetiapine is chemically represented as—

5-HT_(2A) is expressed widely throughout the central nervous system(CNS). It is expressed near most of the serotoninergic terminal richareas, including neocortex (mainly prefrontal, parietal, andsomatosensory cortex) and the olfactory tubercle. Especially, highconcentrations of this receptor on the apical dendrites of pyramidalcells in layer V of the cortex may modulate cognitive processes, workingmemory and attention. In the periphery, it is highly expressed inplatelets and many cell types of the cardiovascular system, infibroblasts, and in neurons of the peripheral nervous system. Theefficacy of Quetiapine in schizophrenia and its mood stabilizingproperties in bipolar depression and mania are mediated throughcombination of dopamine type 2 (D2) and serotonin type 2 (5HT2)antagonism

Physiological processes mediated by the receptor include:

-   -   CNS: neuronal excitation, behavioral effects, learning and        anxiety    -   Smooth muscle: contraction (in gastrointestinal tract & bronchi)    -   Vasoconstriction/vasodilation    -   Platelets: aggregation    -   Activation of the 5-HT_(2A) receptor with        1-[2,5-dimethoxy-4-iodophyryl]-2-amino propane hydrochloride        (DOI), produces potent anti-inflammatory effects in several        tissues including cardiovascular and gut. Other 5-HT_(2A)        agonists like LSD also have potent anti-inflammatory effects        against TNF-alpha-induced inflammation.    -   Activation of the 5-HT_(2A) receptor in hypothalamus causes        increases in hormonal levels of oxytocin, prolactin, ACTH,        corticosterone, and renin.    -   Role in memory

Unless specified to the contrary, the term “Quetiapine” embraces boththe free base and pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts are salts that retain the desiredbiological activity of the parent compound and do not impart undesirabletoxicological effects. Examples of such salts are acid addition saltsformed with inorganic acids, for example, hydrochloric, hydrobromic,sulfuric, phosphoric, and nitric acids and the like; salts formed withorganic acids such as acetic, oxalic, tartaric, succinic, maleic,fumaric, gluconic, citric, malic, methanesulfonic, ptoluenesulfonic,napthalenesulfonic, and polygalacturonic acids, and the like; saltsformed from elemental anions such as chloride, bromide, and iodide;salts formed from metal hydroxides, for example, sodium hydroxide,potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesiumhydroxide; salts formed from metal carbonates, for example, sodiumcarbonate, potassium carbonate, calcium carbonate, and magnesiumcarbonate; salts formed from metal bicarbonates, for example, sodiumbicarbonate and potassium bicarbonate; salts formed from metal sulfates,for example, sodium sulfate and potassium sulfate; and salts formed frommetal nitrates, for example, sodium nitrate and potassium nitrate.Pharmaceutically acceptable and non-pharmaceutically acceptable saltsmay be prepared using procedures well known in the art, for example, byreacting a sufficiently basic compound such as an amine with a suitableacid comprising a physiologically acceptable anion. Alkali metal (forexample, sodium, potassium, or lithium) or alkaline earth metal (forexample, calcium) salts of carboxylic acids can also be made.Pharmaceutically acceptable cations include the cationic component ofthe acids listed above. Pharmaceutically acceptable anions include theanionic component of the bases listed above. In some preferredembodiments, Quetiapine (or a derivative thereof) is formulated as thesalt, for instance the fumarate salt. Acids like fumaric acid, becausethey contain two acidic protons, may form salts with quetiapine in a 1:1or 2:1 (quetiapine:acid) stoichiometric ratio.

Pharmaceutically acceptable esters include those in which the estergroup can be cleaved subsequent to administration and absorption of thequetiapine ester. Esters may be formed through the primary hydroxylgroup in quetiapine and a suitable carboxylic acid, and have thefollowing structure:

wherein R can be an optionally substituted C₁₋₆alkyl group (e.g.,methyl, ethyl, propyl, etc). Suitable substituents include hydroxyl,amino, or 1-yl-morpholino groups. In some cases, the ester can be formedusing an amino acid, in which cases R is a group of the formula:CH(NH₂)R¹, wherein R¹ can be hydrogen or an optionally substitutedC₁₋₆alkyl group (e.g, methyl, isopropyl, isobutyl, 3-aminopropyl,benzyl, or 1-mercaptomethyl. Suitable amino acid based esters can beformed from alanine, arginine, asparagine, aspartic acid, cysteine,glutamic acid, glutamine, glycine, histidine, isoleucine, leucine,lysine, methionine, phenylalanine, proline, pyrrolysine, selenocysteine,serine, threonine, tryptophan, tyrosine and valine.

The term “treating” or “treatment” as used herein comprises a treatmentrelieving, reducing or alleviating at least one symptom in a subject oreffecting a delay of progression of a disease. For example, treatmentcan be the diminishment of one or several symptoms of a disorder orcomplete eradication of pulmonary arterial hypertension. Within themeaning of the present invention, the term “treat” also includes toarrest, delay the onset (i.e., the period prior to clinicalmanifestation of a disease) and/or reduce the risk of developing orworsening a disease. The term “combination” as used herein, defineseither a fixed combination in one dosage unit form, a non-fixedcombination or a kit containing individual parts for combinedadministration.

Pulmonary hypertension can be classified as either primary or secondary.When the arterial hypertension is not accompanied or caused by anotherunderlying heart or lung disease or condition, it is called primarypulmonary arterial hypertension. When the arterial hypertension istriggered by another disease state, it is designated secondary aterialpulmonary hypertension. Exemplary conditions which can cause secondarypulmonary hypertension include congenital heart defects, ventricular oratrial septal defects/holes, which are in some cases called Eisenmengercomplex, as well as valve conditions such as stenosis.

Pulmonary hypertension can be associated with left heart disease, orright heart disease. In some embodiments, Quetiapine (or a derivativethereof) can be used to treat pulmonary hypertension associated withleft heart disease, whereas in other embodiments, Quetiapine (or aderivative thereof) can be used to treat pulmonary hypertensionassociated with right heart disease. In further embodiments, Quetiapine(or a derivative thereof) can be used to treat pulmonary hypertensionassociated with both right and left heart disease. Quetiapine can beused to treat patients with sporadic idiopathic PAH, heritable PAH, aswell as PAH due to disease of small pulmonary muscular arterioles.

Disclosed herein are methods for treating patients with pulmonaryarterial hypertension. The hypertension may be mild (resting arterialpressure between 14-25 mm Hg) or complete (resting arterial pressuregreater than 25 mm Hg). The patient to be treated may have a pulmonaryarterial pressure greater than 14 mm Hg, greater than 16 mm Hg, greaterthan 18 mm Hg, greater than 20 mm Hg, greater than 22 mm Hg, greaterthan 24 mm Hg, greater than 26 mm Hg, greater than 28 mm Hg, greaterthan 30 mm Hg, greater than 32 mm Hg, greater than 34 mm Hg, greaterthan 36 mm Hg, greater than 38 mm Hg, or greater than 40 mm Hg.

In some embodiments, Quetiapine (or a derivative thereof) isadministered to a patient (which may be a human or other mammal) in anamount sufficient to cause at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%,or 40% reduction in resting arterial pressure relative to the pulmonaryarterial pressure prior to commencing treatment. In some instances,Quetiapine (or a derivative thereof) is administered at a dose effectivesuch that the patient's final resting arterial pressure is about 25 mmHg, about 24 mm Hg, about 23 mm Hg, about 22 mm Hg, about 21 mm Hg,about 20 mm Hg, about 19 mm Hg, about 18 mm Hg, about 17 mm Hg, about 16mm Hg, about 15 mm Hg, or about 14 mm Hg. In certain embodiments,Quetiapine (or a derivative thereof) is administered in combination withother agents, as described below, to achieve these therapeutic outcomes.

Pulmonary hypertension can be characterized by a pulmonary bloodpressure greater than about 25 mm Hg at rest, and 30 mm Hg duringexercise. Normal pulmonary arterial pressure is about 14 mm Hg at rest.In certain embodiments, Quetiapine (or a derivative thereof) can be usedto treat patients having a resting pulmonary arterial pressure of atleast 20 mm Hg, at least 25 mm Hg, at least 30 mm Hg, at least 35 mm Hg,at least 40 mm Hg, at least 45 mm Hg, at least 50 mm Hg, at least 55 mmHg, or at least 60 mm Hg.

In some instances, the Quetiapine may be administered to a patient asingle time, while in other cases Quetiapine can be administered usingan intervallic dosing regimen. For instance, Quetiapine may beadministered once, twice, or three times a day for a period at least 1week, for example 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 20weeks, 40 weeks, or 52 weeks. In some instances, Quetiapineadministration can be suspended for some period of time (e.g., 1, 2, 3,4, 6, 8, 10, 20, 40 or 52 weeks) followed by another period ofadministration.

In some instances, an initial dosage (higher dose, relative tomaintenance dose) and maintenance doses (lower dose, relative to initialdose) may be specified. For instance, an initial dosage may beadministered over the course of 1, 3, 5, 7, 10, 14, 21 or 28 days,followed by a maintenance dosage which is administered for the durationof the treatment. In some instances, the Quetiapine can be administeredto the patient using an interval greater than a day. For instance, theQuetiapine can be administered once every other day, once every thirdday, once a week, once every two weeks, once every four weeks, once amonth, once every other month, once every third month, once every sixmonths, or once a year. In some instance injectable formulations, suchas depot formulations, are suitable for dosing regimens with extendedperiods in between administration, however, oral formulations can alsobe used in such systems.

The dosage and dosage regimen may be calculated per kg body weight. Thedosage regimen may vary from a day to a month. Preferably, thecomposition as contemplated by the invention may be administered atleast once, twice or thrice a day in the dosing range from 0.05 mg toabout 20 mg per kg per day, 0.1 mg to about 10 mg per kg per day, 0.5 mgto about 10 mg per kg per day, 0.5 mg to about 5 mg per kg per day, 1 mgto about 5 mg per kg per day, or as per the requirement of the patientto be treated.

In some instances, the Quetiapine (or a derivative thereof) may beadministered to a patient a single time, while in other cases Quetiapine(or a derivative thereof) can be administered using an intervallicdosing regimen. For instance, Quetiapine (or a derivative thereof) maybe administered once, twice, or three times a day for a period at least1 week, for example 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 20weeks, 40 weeks, or 52 weeks. In some instances, Quetiapine (or aderivative thereof) administration can be suspended for some period oftime (e.g., 1, 2, 3, 4, 6, 8, 10, 20, 40 or 52 weeks) followed byanother period of administration.

Preferably, Quetiapine (or a derivative thereof) may be provided in theform of a pharmaceutical composition such as but not limited to, unitdosage forms including tablets, capsules (filled with powders, pellets,beads, mini-tablets, pills, micro-pellets, small tablet units, multipleunit pellet systems (MUPS), disintegrating tablets, dispersible tablets,granules, and microspheres, multiparticulates), sachets (filled withpowders, pellets, beads, mini-tablets, pills, micro-pellets, smalltablet units, MUPS, disintegrating tablets, dispersible tablets,granules, and microspheres, multiparticulates), powders forreconstitution, transdermal patches and sprinkles, however, other dosageforms such as controlled release formulations, lyophilized formulations,modified release formulations, delayed release formulations, extendedrelease formulations, pulsatile release formulations, dual releaseformulations and the like. Liquid or semisolid dosage form (liquids,suspensions, solutions, dispersions, ointments, creams, emulsions,microemulsions, sprays, patches, spot-on), injection preparations,parenteral, topical, inhalations, buccal, nasal etc. may also beenvisaged under the ambit of the invention.

In some instances, Quetiapine (or a derivative thereof) can beadministered by inhalation, for instance as a powder or aerosolizableformulation.

The bioavailability of the drug in a composition, depends on variousattributes of the drug as well as the other inactive ingredients in theformulation. The particle size of the drug is one of such attribute thatmay affect the bioavailability of the drug, when administered to apatient. The particle size may thus be adjusted as per the requirementsof the invention.

The inventors of the present invention have also found that thesolubility properties of Quetiapine (or a derivative thereof) may beimproved by nanosizing thus leading to better bioavailability and dosereduction of the drug.

In one embodiment, Quetiapine (or a derivative thereof) may be presentin the form of nanoparticles which have an average particle size of lessthan 2000 nm, less than 1500 nm, less than 1000 nm, less than 750 nm, orless than 500 nm.

Suitable excipients may be used for formulating the dosage formsaccording to the present invention such as, but not limited to, surfacestabilizers or surfactants, viscosity modifying agents, polymersincluding extended release polymers, stabilizers, disintegrants or superdisintegrants, diluents, plasticizers, binders, glidants, lubricants,sweeteners, flavoring agents, anti-caking agents, opacifiers,anti-microbial agents, antifoaming agents, emulsifiers, bufferingagents, coloring agents, carriers, fillers, anti-adherents, solvents,taste-masking agents, preservatives, antioxidants, texture enhancers,channeling agents, coating agents or combinations thereof.

In some instances, the Quetiapine (or a derivative thereof) can beadministered to the patient using an interval greater than a day. Forinstance, the Quetiapine (or a derivative thereof) can be administeredonce every other day, once every third day, once a week, once every twoweeks, once every four weeks, once a month, once every other month, onceevery third month, once every six months, or once a year. In someinstance injectable formulations, such as depot formulations, aresuitable for dosing regimens with extended periods in betweenadministration, however, oral formulations can also be used in suchsystems.

In some embodiments, pulmonary arterial hypertension can be alleviatedor treated by administration of Quetiapine (or a derivative thereof) incombination with one or more other drugs either simultaneously,sequentially, or separately.

Preferably, one or more standard of care drugs that may be envisagedunder the scope of the present invention may comprise from categories offor the treatment of pulmonary hypertension such as, but not limited tophosphodiesterase inhibitors, endothelin receptor antagonist, Inotropicagents, and stimulators of soluble guanylate cyclase, such as riociguat.

Specifically, one or more standard of care drugs include but not limitedto sildenafil, tadalafil, bosentan, ambrisentan, macitentan, nifedipine,diltiazem, digoxin. There are others which dilate the pulmonary arteriesand prevent blood clot formation. Examples of such drugs areEpoprostenol (Veletri, Flolan), treprostinil sodium (Remodulin, Tyvaso),iloprost (Ventavis); PDE 5 inhibitors such as Sildenafil (Revatio),tadalafil (Adcirca), relaxes pulmonary smooth muscle cells, which leadsto dilation of the pulmonary arteries.

The use of Quetiapine may preferably be associated with one or more ofthe above referenced drugs as a combination therapy (either of the samefunctional class or other) depending on various factors like drug-drugcompatibility, patient compliance and other such factors wherein thesaid combination therapy may be administered either simultaneously,sequentially, or separately for the treatment of PAH.

Quetiapine (or a derivative thereof) may be provided with one or moredrugs in the form of a kit, wherein the kit includes Quetiapine and atleast one other drug, and instructions for their administration to a PAHpatient.

In certain embodiments, the administration of Quetiapine (or aderivative thereof), either alone or in combination with one or moredrugs selected from but not limited to phosphodiesterase inhibitors suchas sildenafil, tadalafil etc., endothelin receptor antagonist such asbosentan, macitentan etc. and stimulators of soluble guanylate cyclasesuch as riociguat. In certain embodiments, Quetiapine (or a derivativethereof) can be co-administered with one or more additional agentseffective to lower pulmonary hypertension. In some embodiments theco-administration includes a unitary dosage form containing Quetiapine(or a derivative thereof) and at least one more agent. In otherembodiments, Quetiapine (or a derivative thereof) is administeredseparately from the other agent(s). The additional agent can be a PDE-5inhibitor, for example, avanafil, lodenafil, mirodenafil, sildenafil,tadalafil, vardenafil, udenafil, zaprinast, or icariin. Other agentsinclude calcium channel blockers like dihydropyridines (e.g.,amlodipine, nifefipine) and diltiazem; prostacyclin pathway agonistssuch as epoprostenol, treprostinil, iloprost, and selexipag; endothelinreceptor antagonists such as bosentan, macitentan, ambrisentan,andsitaxsentan; guanylate cyclase stimulators such as riociguat;diuretics; toprimate; fusadil; or anti-coagulants like warfarin.

It may be well appreciated by a person skilled in the art that thepharmaceutical composition comprising Quetiapine in combination with oneor more drugs may require specific dosage amounts and specific frequencyof administrations specifically considering their individual establisheddoses, the dosing frequency, patient adherence and the regimen adopted.As described herein, considering that there are various parameters togovern the dosage and administration of the combination composition asper the present invention, it would be well acknowledged by a personskilled in the art to exercise caution with respect to the dosage,specifically, for special populations associated with other disorders.

EXAMPLES

The following examples are set forth below to illustrate the methods andresults according to the disclosed subject matter. These examples arenot intended to be inclusive of all aspects of the subject matterdisclosed herein, but rather to illustrate representative methods,compositions, and results. These examples are not intended to excludeequivalents and variations of the present invention, which are apparentto one skilled in the art.

Efforts have been made to ensure accuracy with respect to numbers (e.g.,amounts, temperature, etc.) but some errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in ° C. or is at ambient temperature, and pressure is ator near atmospheric. There are numerous variations and combinations ofreaction conditions, e.g., component concentrations, temperatures,pressures, and other reaction ranges and conditions that can be used tooptimize the product purity and yield obtained from the describedprocess. Only reasonable and routine experimentation will be required tooptimize such process conditions.

Example 1—Pulmonary Arterial Hypertension Efficacy Model: MonocrotalineRat

The studies were conducted for hemodynamic evaluation of quetiapine inanesthetized sprague dawley rats treated with monocrotaline (“MCT”) toinduce pulmonary arterial hypertension. Sildenafil was used as aninternal control to compare the effects of Quetiapine.

The effects of Quetiapine were evaluated in rats with monocrotalineinduced pulmonary arterial hypertension using sildenafil as standardcare treatment. Male Sprague-Dawley rats were orally administeredvehicle, Quetiapine (40 mg/kg, divided into a BID regimen given everyday for 28 days starting on Day 1), or sildenafil (100 mg/kg,administered once daily) (n=12 in each group). Rats received a singleinjection of monocrotaline (50 mg/kg, s.c.) on Study Day 1. On thetwenty-eighth day following monocrotaline dosing, the rats wereanesthetized with ketamine/xylazine for terminal monitoring of pulmonaryand systemic arterial pressures along with heart rate.

Test Item: Vehicle (0.5% Methylcellulose+0.2% Tween 80 in deionizedwater, Quetiapine (40 mg/kg dib for 28 days; Sildenafil (1000 mg/kg,administered once daily)

Route of Administration: Oral

* is 0.5% methyl cellulose+0.2% Tween 80 in deionized water

Study Design: The study was planned and conducted according to designdepicted below in Table 1

TABLE 1 Study Design Group No Group Name N MCT (S.C) Test Compound Dose(P.O) Dosing Group I Negative 12 — Vehicle 1 mL/kg QD control Group IIControl 12 50 mg/kg MCT — — Group III Positive 12 50 mg/kg Vehicle 1mL/kg QD Control Group IV Test 12 50 mg/kg Quetiapine 40 mg/kg  BIDGroup V Standard 12 50 mg/kg Sildenafil 100 mg/kg  QD

Male Sprague-Dawley rats in groups I, II, III and IV and V wereadministered 50 mg/kg of body weight of Monocrotaline in DMSOsubcutaneously to induce PAH on day 1. The DMSO group (Group I, negativecontrol) received a single dose of DMSO subcutaneously on day 1. Thevehicle group received 5 ml of vehicle every morning. The Quetiapine aswell as sildenafil groups were orally administered Quetiapine (40 mg/kg,divided into a BID regimen given every day for 28 days starting on Day1), or sildenafil (100 mg/kg, administered once daily). On thetwenty-eighth day after monocrotaline dosing, the rats were anesthetizedwith ketamine/xylazine for terminal monitoring of pulmonary and systemicarterial pressures along with heart rate.

Observation: There were differences in systolic and mean pulmonaryarterial pressures after 28 days in rats treated with Quetiapine at 40mg/kg/day given bid as compared to the vehicle group.

Results: Body weights among the vehicle and treatment cohorts were notsignificantly different at Study Day 28. There were differences insystolic and mean pulmonary arterial pressures after 28 days in ratstreated with 40 mg/kg/bid Quetiapine compared to the vehicle group.

The results are depicted in Table 2 (Right Ventricular SystolicPressure); Table 3 (Right Ventricular Pressure) and Table 4 (Fultonindex: Hypertrophy (RV/LV+S))

TABLE 2 Right Ventricular Systolic Pressure Right Ventricular SystolicPressure (RVSP) mmHg Quetiapine Sildenafil Negative Positive (40 mg/Kg(100 Control Control Control bid) mg/kg) 20.652 58.059 70.816 37.04534.262 25.143 81.052 61.444 44.925 25.579 17.995 57.290 77.630 54.14033.864 27.854 78.538 59.801 47.463 23.627 25.161 62.606 72.949 43.05231.322 21.357 60.018 60.142 36.213 24.486 20.936 72.695 56.082 41.51529.450 23.622 57.327 68.670 68.747 31.316 24.461 54.503 32.922 25.58026.098 20.773 Mean 23.303 65.948 65.942 47.511 29.648 SD 2.907 9.9287.613 10.268 4.106 SE 0.839 3.510 2.692 3.423 1.369 Values are expressedas mean ± SE and analysed by one way ANOVA followed by Tukey’s multiplecomparison post-test. * P < 0.05, ** P < 0.01, *** P < 0.001 as comparedto control, + P < 0.05, ++ P < 0.01, +++ P < 0.001 as compared topositive control

TABLE 3 Right Ventricular Pressure Right Ventricular Systolic Pressure(RVSP) mmHg Quetiapine Sildenafil Negative Positive (40 mg/Kg (100Control Control Control bid) mg/kg) 9.656 30.124 32.476 18.440 12.94712.987 36.451 30.376 20.951 12.352 9.102 27.676 37.232 27.940 16.80416.666 33.807 31.187 21.646 11.481 12.701 29.169 30.585 22.967 15.2269.210 30.734 31.389 16.792 11.673 8.251 29.384 28.909 19.956 14.42711.448 28.386 31.214 24.109 14.139 12.402 28.929 16.310 12.866 10.9479.645 Mean 11.323 30.716 31.671 22.414 13.929 SD 2.361 2.967 2.466 4.0671.951 SE 0.682 1.049 0.872 1.356 0.650 Values are expressed as mean ± SEand analysed by one way ANOVA followed by Tukey’s multiple comparisonpost-test. * P < 0.05, ** P < 0.01, *** P < 0.001 as compared tocontrol, + P < 0.05, ++ P < 0.01, +++ P < 0.001 as compared to positivecontrol

TABLE 4 Fulton index: Hypertrophy (RV/LV + S) Right Ventricular SystolicPressure (RVSP) mmHg Quetiapine Sildenafil Negative Positive (40mg/Kg(100 Control Control Control bid) mg/kg) 0.181 0.619 0.604 0.378 0.3300.179 0.482 0.499 0.334 0.167 0.166 0.493 0.518 0.534 0.354 0.180 0.4710.534 0.458 0.367 0.206 0.588 0.614 0.438 0.297 0.200 0.426 0.508 0.3560.323 0.202 0.513 0.483 0.336 0.312 0.211 0.494 0.446 0.601 0.352 0.1620.289 0.309 0.228 0.213 0.231 Mean 0.197 0.511 0.526 0.414 0.312 SD0.023 0.063 0.058 0.103 0.059 SE 0.007 0.022 0.020 0.034 0.020 Valuesare expressed as mean ± SE and analysed by one way ANOVA followed byTukey’s multiple comparison post-test. * P < 0.05, ** P < 0.01, *** P <0.001 as compared to control, + P <0.05, ++ P < 0.01, ++ P < 0.001 ascompared to positive control.

TABLE 5 Right Ventricle Right Ventricle (RV) (g) Quetiapine SildenafilNegative Positive (40 mg/Kg (100 Control Control Control bid) mg/kg)0.160 0.337 0.378 0.276 0.261 0.178 0.336 0.320 0.190 0.083 0.127 0.2270.300 0.336 0.236 0.140 0.327 0.390 0.337 0.440 0.180 0.347 0.419 0.3120.228 0.180 0.349 0.322 0.260 0.207 0.190 0.317 0.387 0.193 0.232 0.1770.386 0.333 0.353 0.308 0.124 0.225 0.229 0.185 0.170 0.205 Mean 0.1680.328 0.356 0.276 0.247 SD 0.025 0.046 0.043 0.063 0.094 SE 0.007 0.0160.015 0.021 0.031 Values are expressed as mean ± SE and analysed by oneway ANOVA followed by Tukey’s multiple comparison post-test. * P < 0.05,** P < 0.01, *** P < 0.001 as compared to control, + P <0.05, ++ P <0.01, +++ P < 0.001 as compared to positive control.

TABLE 6 Right Ventricle/Body Weight Right Ventricle (RV) (g) QuetiapineSildenafil Negative Positive (40 mg/Kg (100 Control Control Control bid)mg/kg) 0.0004 0.0010 0.0012 0.0008 0.0007 0.0004 0.0010 0.0009 0.00060.0003 0.0003 0.0009 0.0009 0.0010 0.0007 0.0004 0.0009 0.0012 0.00100.0009 0.0004 0.0010 0.0012 0.0010 0.0006 0.0004 0.0009 0.0008 0.00070.0006 0.0004 0.0008 0.0009 0.0006 0.0006 0.0005 0.0009 0.0008 0.00120.0007 0.0003 0.0006 0.0006 0.0004 0.0004 0.0004 Mean 0.0004 0.00090.0010 0.0008 0.0006 SD 0.0000 0.0001 0.0002 0.0002 0.0002 SE 0.00000.0000 0.0001 0.0001 0.0001 Values are expressed as mean ± SE andanalysed by one way ANOVA followed by Tukey’s multiple comparisonpost-test. * P < 0.05, ** P < 0.01, *** P < 0.001 as compared tocontrol, + P <0.05, ++ P < 0.01, +++ P < 0.001 as compared to positivecontrol

The results suggest that Quetiapinie activity in controlling or reducingPAH was found to be comparable among with Sildenafil activity.

Example 2: Quetiapine Fumarate Tablet Composition

Sr. Qty/Tab No. Ingredients (mg) 1 Quetiapine Fumarate 10-500 2Microcrystalline cellulose 10-200 3 Dicalcium Phosphate 50-200 4Croscarmellose Sodium  2-20 5 Povidone  3-25 6 Polysorbate 80  3-10 7Methylene chloride/water q. s. 8 Hypromellose 30-90 9 Colloidal silicondioxide  1-5 10 Talc  1-5 11 Magnesium Stearate  1-5 Coating 12 Opadryready mix 10-20 13 Purified water q. s.

Manufacturing Process

-   1. Microcrystalline cellulose, Dibasic calcium Phosphate and    Croscarmellose sodium were sifted through #35 sieve (500 microns)    and collected in a polyelylene bag.-   2. Quetiapine fumarate was sifted through #60 sieve (250 micron) and    collected in a polyelylene bag.-   3. The materials of step 1 & 2 were loaded in a suitable mixer    granulator (Rapid Mixer Granulator) and mixed for 10 minutes.-   4. Polysorbate-80 solution was prepared by dissolving in    polysorbate-80 in half quantity of methylene chloride/water under    stirring.-   5. Binder solution was prepared by dissolving povidone in remaining    quantity of methylene chloride/water under stirring. Mix the    solution of step to a solution of step 5 under stirring.-   6. The dry mix of step 3 was then granulated with the binder    solution of step 5 in a rapid mixer granulator till the wet mass of    suitable consistency was obtained.-   7. The granules were then dried in a fluidized bed drier a until the    desired LOD was achieved.-   8. Sizing of the dried granules was done by passing through #22    sieve.-   9. Blending of the granules of step 8 with Hypromellose (previously    sifted through 40 #sieve), silicon dioxide (sifted through #80    sieve) and talc (sifted through #80 sieve) for 10-15 minutes in an    octagonal blender.-   10. The required quantity of Magnesium stearate was weighed and    sifted through #80 sieve and added to the blend of step 9 and    blended for 3-7 minutes.-   11. The blend of step 10 was then compressed in to tablets using    suitable punches using tablet compression machine.-   12. The compressed tablets were then film coated with Opadry ready    mix using a tablet coating machine.

Example 3: Quetiapine Fumarate Extended Release Tablets

Sr. Qty No Ingredients (mg/tab) 1. Quetiapine Fumarate  10-500 2Microcrystalline cellulose  75-200 3. Lactose  75-200 4. Povidone  4-165. Corn Starch  10-45 6. Purified water Q. s. 7. Hypromellose (HPMC K4M/150-750 K15 M/K100 M) 8. Colloidal silicon dioxide  1-6 9. Talc  3-1210. Magnesium Stearate  3-12 11 Ready mix opadry  5-10 12 Purified waterQ. s.

Manufacturing Process

-   1. Binder solution was prepared by dissolving Povidone in purified    water.-   2. Quetiapine fumarate, Microcrystalline cellulose, Lactose and    Hypromellose were sifted through #30 mesh sieve.-   3. The sifted materials of step 2 were then placed in rapid mixer    granulator and dry mixing carried out for 10 mins.-   4. The dry mix was further granulated using the binder of step 1.-   5. Granules were then dried in a fluid bed drier until the desired    LOD was achieved.-   6. Sizing of the granules was done by passing the dried granulator    through multimill.-   7. The dried sized granules were then blended with Colloidal silicon    dioxide and talc (pre-sifted through #80 sieve) followed by    lubrication with magnesium stearate (pre-sifted through #80 sieve)    in an Octagonal blender.-   8. The lubricated blend was then compressed into tablets using    suitable tooling using a tablet compression machine.-   9. The tablets were further film coated using a film coating    dispersion. (The film coating dispersion was prepared by dispersing    the Opadry dry mix in purified water).

Example 4: Quetiapine Fumarate Tablets

Sr. Quantity No. Ingredients mg/tablet 1. Quetiapine Fumarate   10-5002. Carnauba wax   30-300 3. Glyceryl dibehenate   10-60 4. Colloidalsilicon dioxide 0.25-2.5 5. Magnesium stearate   3-10 6. Surelesecoating (Colorcon)   5-25 7. Purified water QST

Manufacturing Process

-   1. Quetiapine is mixed with carnauba wax and hot melt granulated.-   2. The granulate of step 1 is then milled.-   3. The milled granules are then blended with colloidal silicon    di-oxide and magnesium stearate.-   4. The blend was then compressed into tablets using a tablet    compression machine-   5. The compressed tablets were further coated using Surelese coating    dispersion in purified water in a suitable coating machine.

Example 5: Quetiapine Fumarate Delayed Release Tablets

Sr. Quantity No. Ingredients mg/tablet Granulation 1. QuetiapineFumarate   10-500 2. Povidone   10-60 3. Stearic acid  2.5-100 Coating0.25-2.5 4. Ethocel PR 100 (Ethylcellulose)   5-25 5 Povidone   5-15 6.Polyethylene glycol 1450  2.5-10 7. Denatured alcohol Q. s.

Manufacturing Process

-   1. Povidone was dissolved in water.-   2. Quetiapine was placed in top-spray assembly of the Fluid bed    processor (GPCG 1-1).-   3. Povidone solution was then sprayed on to the active to form    granules.-   4. Sizing of the granules was done by passing through the suitable    sieve.-   5. Stearic acid was weighed and sifted through a suitable sieve.-   6. The milled granules were then blended with stearic acid in a    suitable blender.-   7. The blend was then compressed into tablets using a tablet    compression machine-   8. The compressed tablets were further coated using Surelese coating    dispersion in purified water in a suitable coating machine

Example 6: Powder for Oral Suspension

Sr. Quantity No. Ingredients mg/ml 1. Quetiapine Fumarate   10-500 2.Xylitol  100-400 3. Citric acid monohydrate   1-10 4. Sucralose  0.1-7.55 Xanthan gum  0.1-1.0 6. Talc 0.25-2.5 7. Magnesium stearate  0.5-2.58. Colloidal silicon dioxide   5-10 9. Artificial Cherry Flavour   5-10

Manufacturing Process

-   1. Quetiapine fumarate was sifted through sieve #60 and collected in    a polyethylene bag-   2. Xylitol and citric acid monohydrate was weighed and sifted    through sieve #40 and collected in a suitable polybag-   3. Sucralose, xanthan gum, Artificial cherry flavor were sifted    through sieve #60 and collected in a suitable polyethylene bag-   4. Talc, Magnesium stearate, and colloidal silicon-di-oxide were    sifted through sieve #80 and collected in a polyethylene bag-   5. The quetiapine fumarate, Xylitol, Citric acid monohydrate,    Sucralose, Xanthan gum, Talc and colloidal silicon dioxide were    placed in a suitable blender and blended for 10 minutes.-   6. Artificial cherry flavor and magnesium stearate was added to the    blend of step 5 and further blended for 5 minutes.-   7. The blend was then filled in high density HDPE bottles and sealed    with CRC caps using induction sealer.

Example 7: Quetiapine Soft Gelatin Capsule Composition

Sr. Qty. No. Ingredient mg/unit 1. Quetiapine Fumarate  20-400 2.D-alpha-tocopheryl polyethylene 250-550 glycol 1000 succinate (TPGS) 3.Polyethylene glycol 400 250-400 4. Polyethylene glycol 400  25-40

Manufacturing Process

-   1. D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was    loaded in a suitable stainless steel-jacketed vessel and heated to    50° C. until liquefied.-   2. Polyethylene glycol 400 (90%) was heated in a separate stainless    steel vessel to 50° C. and added to the liquefied material of step 1    slowly.-   3. The ingredients were mixed using a suitable stirrer until    homogenous solution obtained.-   4. The temperature of the homogenous solution was increased to 65°    C., and Quetiapine Fumarate was added to the solution under constant    stirring and dissolved.-   5. Remaining quantity of Polyethylene glycol 400 (10%) was added to    the solution of step 4 and the solution cooled to room temperature.-   6. Vacuum was applied to remove the entrapped air.-   7. The mixture was then filled using white opaque soft gelatin    capsules (size 12, oblong) using a capsule-filling machine. The    capsules were further dried to a moisture level of 3-6% and shell    hardness of 7-10 N and packed in a suitable container.

Example 8: Oral Suspension

Sr. Quantity No. Ingredients mg/mL 1. Quetiapine Fumarate   10-500 2.Ascorbic acid   5-15 3. Edetate di sodium  0.2-2.0 (sodium EDTA) 4.Saccharin sodium  0.1-1.0 5. Sodium metabisulfite   1-5 (sodiumdisulfite) 6. Propylene glycol   75-150 7. Sorbitol (70% solution)  75-150 8. Glycerin (glycerol)  200-350 9 Sucrose  250-400 10.Quinoline yellow 0.01-0.1 11. Pineapple flavor  0.1-0.5 12. Purifiedwater q.s

Manufacturing Process

-   1. Purified water (˜25% of total quantity required) was added to a    manufacturing vessel and heated to 90° C. to 95° C.-   2. Required quantity of sucrose was added to the heated water of    step 1 under slow mixing (temperature maintained at 90° C. to 95°    C.). Mixing was continued for 1 hr.-   3. Propylene glycol, sorbitol (70% solution) glycerin was added to    the mixture of step 2 and mixed at high speed for 10 minutes.-   4. The mixture was allowed to cool to a temperature of 50° C. with    continuous mixing at slow speed.-   5. Quetiapine fumarate was added to the solution of step 4 with    continuous mixing at high speed for 30 minutes until a uniform    suspension was obtained.-   6. Ascorbic acid, edetate disodium and sodium metabisulfite were    added to the suspension of step 4 with continuous mixing.-   7. Pineapple flavor was dissolved in part quantity of purified water    and added to suspension of step 4 with continuous mixing.-   8. Saccharin sodium were dissolved in part quantity of purified    water and added to the suspension of step 4 with continuous mixing.-   9. Quinoline yellow was dissolved in part quantity of purified water    and the colour solution was transferred to the suspension of step 4    with continuous mixing.-   10. Rinsing of the container of colour solution was done with    purified water and rinsings added to the Suspension of step 4. The    mixture was mixed at high speed for 5 minutes.-   11. Volume makeup was done with purified water and solution was    again mixed for 20 minutes at high speed.-   12. pH of the suspension was checked and recorded (limit: 6.0-8.2).    If required, pH was adjusted with 10% citric acid or 10% sodium    citrate solution.-   13. The suspension was then filled in suitable bottles.

Example 9: Capsule Composition

Sr. Qty No Ingredients (mg/tab) Core pellets 1 Quetiapine Fumarate  10-500 2 Microcrystalline cellulose   75-200 3 Lactose   75-200 5Povidone  2.5-10 6 Purified water Q. s. Seal coating 7 Hypromellose  15-40 8 Triethyl citrate 0.25-2.5 9 Isopropyl alcohol QS Functionalcoating 10 Ethyl cellulose   20-60 11 Triethyl citrate 0.25-2.5 12 Talc  3-12 13 Isopropyl alcohol Q. s. 14 Purified water Q. s.

Manufacturing Process

-   1. Quetiapine fumarate, Microcrystalline cellulose, Lactose were    sifted through #40 mesh sieve.-   2. The sifted materials of step 2 were then placed in planetary    mixer and dry mixing was done for 10 minutes.-   3. Binder solution was prepared by dissolving Povidone in purified    water and wetting of the mass was done by adding the binder solution    to the dry mixture blend of step 3.-   4. The wet mass of step 3 was then passed through extruder to form    cylindrical shaped extrudates.-   5. The extrudates were then places in a spheronizer to form pellets.-   6. Pellets were then dried in a fluid bed drier until the desired    LOD was achieved.-   7. Seal coating solution was prepared by dissolving HPMC, PVP and    Triethyl citrate in a mixture of Isopropyl alcohol and purified    water-   8. Pellets were then seal-coated with a seal coating solution using    fluid bed processor fitted with a bottom spray assembly.-   9. The seal coated pellets were further coated with ethyl cellulose    dispersion-   10. Functional coating dispersion was prepared by dissolving ethyl    cellulose and triethyl citrate in isopropyl alcohol, talc was    dispersed in purified water and this dispersion was then added to    the ethylcellulose solution to form a coating dispersion.-   11. Seal coated pellets were then coated with ethyl cellulose    dispersion using a fluid bed processor fitted with a bottom spray    assembly.-   12. The coated pellets were then filled in capsules.

The compositions and methods of the appended claims are not limited inscope by the specific compositions and methods described herein, whichare intended as illustrations of a few aspects of the claims and anycompositions and methods that are functionally equivalent are intendedto fall within the scope of the claims. Various modifications of thecompositions and methods in addition to those shown and described hereinare intended to fall within the scope of the appended claims. Further,while only certain representative compositions and method stepsdisclosed herein are specifically described, other combinations of thecompositions and method steps also are intended to fall within the scopeof the appended claims, even if not specifically recited. Thus, acombination of steps, elements, components, or constituents may beexplicitly mentioned herein or less, however, other combinations ofsteps, elements, components, and constituents are included, even thoughnot explicitly stated. The term “comprising” and variations thereof asused herein is used synonymously with the term “including” andvariations thereof and are open, non-limiting terms. Although the terms“comprising” and “including” have been used herein to describe variousembodiments, the terms “consisting essentially of” and “consisting of”can be used in place of “comprising” and “including” to provide for morespecific embodiments of the invention and are also disclosed. Other thanin the examples, or where otherwise noted, all numbers expressingquantities of ingredients, reaction conditions, and so forth used in thespecification and claims are to be understood at the very least, and notas an attempt to limit the application of the doctrine of equivalents tothe scope of the claims, to be construed in light of the number ofsignificant digits and ordinary rounding approaches.

1-14. (canceled)
 15. A pharmaceutical composition comprising quetiapineor a pharmaceutically acceptable salt or ester thereof, and at least oneadditional agent effective to treat pulmonary hypertension.
 16. Thepharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises one or more of phosphodiesterase inhibitors,calcium channel blockers, endothelin receptor antagonists, inotropicagents, prostacyclin pathway agonists, anti-coagulants, guanylatecyclase stimulators, PDE-5 inhibitors, or a combination thereof.
 17. Thepharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises one or more of avanafil, lodenafil,mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, zaprinast,icariin, amlodipine, nifefipine, diltiazem, bosentan, ambrisentan,sitaxsentan, macitentan, riociguat, toprimate, fusadil, warfarin,digoxin, epoprostenol, treprostinil sodium, iloprost, selexipag, or acombination thereof.
 18. A kit comprising quetiapine or apharmaceutically acceptable salt or ester thereof, in an amounteffective to treat pulmonary hypertension, and at least one additionalagent effective to treat pulmonary hypertension.
 19. The kit of claim18, wherein the at least one additional agent comprises one or more ofphosphodiesterase inhibitors, calcium channel blockers, endothelinreceptor antagonists, inotropic agents, prostacyclin pathway agonists,anti-coagulants, guanylate cyclase stimulators, PDE-5 inhibitors, or acombination thereof.
 20. The kit of claim 18, wherein the at least oneadditional agent comprises one or more of avanafil, lodenafil,mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, zaprinast,icariin, amlodipine, nifefipine, diltiazem, bosentan, ambrisentan,sitaxsentan, macitentan, riociguat, toprimate, fusadil, warfarin,digoxin, epoprostenol, treprostinil sodium, iloprost, selexipag, or acombination thereof.
 21. The kit according to claim 18, comprising afirst composition comprising quetiapine or pharmaceutically acceptablesalt or ester thereof, and a second composition comprising the at leastone additional agent effective to treat pulmonary hypertension.
 22. Thepharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises one or more phosphodiesterase inhibitors. 23.The pharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises one or more calcium channel blockers.
 24. Thepharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises one or more endothelin receptor antagonists.25. The pharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises one or more inotropic agents.
 26. Thepharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises one or more prostacyclin pathway agonists.27. The pharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises one or more anti-coagulants.
 28. Thepharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises one or more guanylate cyclase stimulators.29. The pharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises one or more PDE-5 inhibitors.
 30. Thepharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises sildenafil, tadalafil, or a combinationthereof.
 31. The pharmaceutical composition of claim 15, wherein the atleast one additional agent comprises epoprostenol, iloprost,treprostinil sodium, or a combination thereof.
 32. The pharmaceuticalcomposition of claim 15, wherein the at least one additional agentcomprises riociguat.
 33. The pharmaceutical composition of claim 15,wherein the at least one additional agent comprises bosentan,macitentan, ambrisentan, sitaxsentan, or a combination thereof.
 34. Thepharmaceutical composition of claim 15, wherein the at least oneadditional agent comprises amlodipine, nifefipine, diltiazem, or acombination thereof.